title: Discovery of triazine-benzimidazoles as selective inhibitors of mTOR.
abstract: mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model.
authors.affiliation: Medicinal Chemistry, Amgen Inc, 360 Binney St, Cambridge, MA 02142, USA. epeterso@amgen.com
authors.forename: Emily A
authors.initials: EA
authors.lastname: Peterson
authors.forename: Paul S
authors.initials: PS
authors.lastname: Andrews
authors.forename: Xuhai
authors.initials: X
authors.lastname: Be
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Boezio
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Bush
authors.forename: Alan C
authors.initials: AC
authors.lastname: Cheng
authors.forename: James R
authors.initials: JR
authors.lastname: Coats
authors.forename: Adria E
authors.initials: AE
authors.lastname: Colletti
authors.forename: Katrina W
authors.initials: KW
authors.lastname: Copeland
authors.forename: Michelle
authors.initials: M
authors.lastname: DuPont
authors.forename: Russell
authors.initials: R
authors.lastname: Graceffa
authors.forename: Barbara
authors.initials: B
authors.lastname: Grubinska
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kim
authors.forename: Erin L
authors.initials: EL
authors.lastname: Mullady
authors.forename: Philip
authors.initials: P
authors.lastname: Olivieri
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Schenkel
authors.forename: Mary K
authors.initials: MK
authors.lastname: Stanton
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Ti
authors.initials: T
authors.lastname: Cai
authors.forename: Daniel S
authors.initials: DS
authors.lastname: La
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D014227:Triazines; D058570:TOR Serine-Threonine Kinases